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Three-pronged plot to keep HIV at bay

ATTACKING HIV using a combination of anti-retroviral drugs has proved resoundingly successful at keeping the virus at bay. Now an experimental therapy is being proposed that will apply the same concept from within the cells HIV attacks and destroys, by arming the cells to fight the virus on three fronts.

“We don’t want to rely on a single mechanism,” says John Rossi, head of the team developing the therapy at the Beckman Research Institute of the City of Hope in Duarte, California. “So we’ve developed what we call a triple vector against HIV.” If one strategy fails, another will kick in and thwart the virus.

Most people infected with HIV suffer a progressive loss of the white blood cells called CD4+ T-cells. This causes the loss of cellular immunity that eventually leads to AIDS. The idea of the new therapy is to rebuild a patient’s entire blood system from scratch, creating a new population of blood cells that are resistant to infection by HIV and stop the virus replicating if infection does occur.

To do this, Rossi plans to make a strand of DNA containing genes that will manufacture three types of RNA molecule lethal to HIV. A harmless lentivirus will be used to load this “vector” into the DNA of a patient’s own blood cells. Once loaded, the vector will start making the RNA inside the cells.

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The first type of RNA is a ribozyme, a type of enzyme that sabotages the production of a key cell surface receptor protein called CCR5, which HIV uses to gain access to the cell. “That means the virus can knock, but it can’t get in,” says Rossi.

Should the virus breach that defence it faces a second obstacle&colon; a hairpin-shaped RNA molecule made by the vector that latches onto the virus’s genetic material and destroys it before it can insert itself into the patient’s DNA and begin to replicate. Finally, if the virus survives even that, the third type of RNA, designed as a “decoy”, binds to and traps an HIV protein called tat, which normally orchestrates the production of viral protein. Without it HIV can’t replicate and infect further cells.

To get the vector into as many cells as possible, Rossi and his colleagues plan to load it into specialised stem cells from bone marrow that can be extracted from blood samples and have the ability to mature into every type of blood cell. Once re-injected, these cells are expected to out-survive all other blood cells and produce descendants that inherit the vector and so are equally immune to HIV. Ultimately, they could take over the entire blood system and so prevent the devastating loss of immunity associated with AIDS, though the patient would remain infected with HIV and would therefore still be able to pass the virus to others.

Rossi’s team is seeking permission from the US Food and Drug Administration to begin a trial in September in five patients with AIDS-related lymphoma, a type of cancer known to develop when HIV has destroyed the immune system. His ultimate aim is to use the therapy to treat anyone with AIDS. “I envision being able to combine gene therapy with the current drugs combination therapies, making them more powerful,” he says.

These cells are expected to out-survive all other blood cells and produce descendants that are equally immune to HIV

A similar strategy is being planned by Ben Berkhout and his colleagues at the University of Amsterdam in the Netherlands. They plan to engineer stem cells with a combination of four short hairpin RNA molecules, each of which would attack different regions of viral DNA. The hope, as with Rossi’s therapy, is that the stem cells would produce descendants throughout the blood system that are as immune to HIV as the stem cells.